Extraction of lactones



Patented Jan. 10, 195i .EXTRACTIONeOFuLACTONES Rdlanddfiappfliewztrk, Frank-DRFiekeL- F-lemington, and Louis 5!.5 Rosenberg, Ridgefield-Llark, 1., assignors ntoopcoeflhemical Company,

:HarrisonnNjeJ .,:a; corporation of:. New Jersey No Drawing. Original application-DeceniberIS,

1946, Serial'-No.-422,868. Divided and t-his'aipplicati'on January 28, 1947; Se1 ial #No'. 7 2 15922 .1 Claim. .1 This; invention :relatesiin general to the-synthesis: of aldehydes' :and =lactones,--. and more particularly, to the ipreparation .101 :1 a;a-dimethylq fir-h-ydrcxypropionaldehyde and rm -.hydroxy 5,5 dimethyl- +butyrolactone.

Thisv applicationisa division of ear .copending application Serial 1N.o.--.i22;8fi8 filed December 1-3, 1941, now Patent No. 2,434,246, issued January .13, 1948.

With the discovery of the; -physio1ogical.activity .of :pantothenic acid .and the subsequent. determination of..lthe. structure thereof, u-ihydroxw 5,,6-dimethyl y '-Tbutyrolac'tone has become a chemical of major importance. In thesynthesis of pantothenic acid, a hydroxy-fifi-dimethylqbutyrolactone or -the corresponding :a'ci'd 'is cond'ensed with fl-alanine'or a' saltor ester thereof. a dimethyl-e=hydroXyp 1 ionaldehyde is one 'of' the "principal compounds used' in" the synthesis of a hydroXy-fk/i dimethylw-butyrolactone and -the corresponding-acid. -"dime'thyl'- ;8 hy droxypropionaldehyde, and e-hydrexy- 1335 --=dimethyl-y butyrelactone and the "corresponding acid have been known for man-y year sgas have processes for preparing the same. However, the heretofore known processes for prepar ing these compounds' have beenwather inefiicient an'd cost- "ly because of the cumbersomeness of and-length of time required to carry outmertainsteps in ithe processes. The cumbersomeness and lengthin'es-s ofithese :procerlures' havealso tended tollowerith yieldrof .the rfinal products.

0:,c: dimethyl -.,8 hydroxypropionaldehyde ..is usually-prepared by condensing:isohutyraldehyde with formaldehyde. Upon completion of.*the'.reaction, the product is extracted .from the reaction mass with'ethyl ether. .Although' the 38X- traction with ether in this-step is fairlyefiicient, room for vast improvement remains. :Further- .mere, ethyl ether is a highly dangerous material to handle due to its exceedingly high inflammability and explosive character. In the-production of a-hydroxy- 3,;8edimethyl-y-butyrolactone, a,u-.dimethyl- 3ehydroxypropionaldehyde is converted into itsbisulfite-compound which in .turn is converted into the corresponding. cyanohydrin. .The cyanohydrin is then treated With hydrochlo- 'ric acid which converts the cyanohyd'r'in to order to obtain an'efficient recovery-'of'the "tone it is necessary to extract the aqueous' solution with ether continuously for a period of-"from '2 16.1130; 18. hours. Notwithstanding this-prolonged =period-.-o f extraction, the ,yields ia-redar from-abe- King commercially'.-satisfactory. Thus this preiceduresis inefiiacient, as regards the v-yields .ob tained, in addition to..being. tedious, cumbersome and. timeaconsuming. Furthermore, there .-.are .the..- additional hazards involved in :using .such. a solvent asethyl .e.tl:ler,-i. e its extremely high inflammzibility-and .exfilosive character.

.IItisthe obj ect .of..this invention 'toobviate .the foregoing disadvantages inthev synthesis .of -u.-.hychioxyfifi:dimethyl yihutyrolactcineand its-corresponding acid.

H'Aspecific object or this invention is to provide an improved methodo'f eat]:actinglo .dimethyl- .fl-hydro gypropionaldehyde and .a-hydroxy ligfldimethylqflbutyrdladtone from thereactionmass in which they are produced.

"further object or thisiinven'tioniis' tofproiiide meansior. materially reducing the time required tov extract a;hydroxy+ffl,18'-dimethyl-;y-butyrolac tone'fromthe.reaction massiin which .it is pro 'duced while at thesame time 'increa's'ing'the yield of .lactone'obtained and decreasing Ithefire ihazard -involved in "the process.

"()therob'jrects ofthe invention willJin -partbe obvious and will. in part appear hereinafter.

"It has now been discovered that the foregoing and otherobj ects of the invention may he readily 'accomfilished by. emjiloyingv ,halogenatedhydrocarbon. solvents .ingplace of ethyl ether; in. the. ex-

raction of 1 dimethyl phydroxyprobionaldehyde and a hydroxyiifi dimethyl-y butyrolactonei'from the reaction mass in'lvihich they are produced. Not only may'the extraction thus be very eificiently accomplishedlin a minimum of timefbut alsoithe"hazardsfinvolved in the process 'areweryereatly reduced since the halogenated hydrocarbon solvents: employed are in mostinstances .much less inflammable than ethyl "ether. The advantage of using" halogenated hydrocarbons is especially great in the extraction of the -d hydroxyww dimethyl bdtyrolactone since we have found that"substantially "all'of' the lact'one maybeextracteddrom the reaction mass in'-"less than about one-hourwvhiamemploying the "preferred -halogenated-hydrocarbon solventsyarid in only --sli'ghtly*longer than-=onehour-=wlren the less: preferred halogene-ted hydroc'arbon solvents so are used; whereas when-ethyl ether is employed,

from about lfi' hours toabout 18 hours 'are usual- -lyf required to extract substantially all er the-lad tenewhich ca-nbe obtairied' byusin'g ethyl-ether. Moreoverfithe amount of lactone w'hich-is' o'btained when =us'ingether is appreeiably less than that which may be obtained by using a halogenated hydrocarbon solvent.

It is preferred that a halogenated hydrocarbon solvent having a relatively low boiling point, i. e., below 100 0., be employed due to the fact that the removal of the solvent from the aldehyde and from the lactone will thus be simplified since the separation may then be easily accomplished by fractional distillation. Of course solvents which have a boiling point higher than 100 C. may be employed, if desired, provided their boiling points are below those of the aldehyde and the lactone so that the solvents may be separated therefrom by distillation. Since the aldehyde has a tendency to polymerize when heated too vigorously, it is preferred that the solvents used to extract the aldehyde be ones which do not have boiling points in excess of 100 C. since in removing the solvent, even if removing it under reduced pressure, there may be some polymerization'of the aldehyde if the solvent is one which boils at a temperature very much in excess of 100 C. Thus, among the solvents which may be employed there may be mentioned methylene chloride, ethylene dichloride, chloroform, propylene dichloride, trichloroethylene, and similar halogenated hydrocarbon solvents, the first three solvents named being highly preferred.

In carrying out the process of the invention, the synthesis of the a,a-dimethyl-p-hydroxypropionaldehyde and of the a-hydroxy-p,5-dimethyl-v-butyrolactone may be carried out essentially as set forth by Stiller, et al., in the Journal of the American Chemical Society, 62, pages 1785-1790, (1940), or by any other suitable method with the exception that instead of using ethyl ether to extract the u,m-dimethyl-B- hydroxy-propionaldehyde and the u-hydroxy- 18,;3-dimethyl-y-butyrolactone from the reaction masses in which they are produced, a halogenated hydrocarbon solvent, preferably methylene chloride, ethylene dichloride or chloroform, is employed. The actual extraction may be carried out in any suitable manner; thus either a continuous or batch process may be employed. In extracting the lactone with ethyl ether, it is necessary to extract the reaction medium continuously for 16 to 18 hours, whereas when a halogenated hydrocarbon solvent such as those mentioned above is employed, a considerably higher yield of the lactone is obtained with only four or five successive extractions of the reaction mass, which extractions may conveniently be carried out in less than about one hour. Furthermore, as has been previously mentioned, the hazards which are involved in the use of ethyl ether are greatly reduced in most cases when the preferred chlorinated hydrocarbons, particularly methylene chloride and ethylene dichloride, are employed in place of the ethyl ether.

In producin u-hydroxy-p,B-dimethyl-y-butyrolactone by converting the corresponding cyanohydrin to the lactone, a racemic mixture of the lactone is obtained. It is known that pantothenic acid produced by reacting B-alanine or salts or esters thereof with d-a-hydroxy-s,edimethyl-y-butyrolactone has little or no physiological activity; and that in order to obtain pantothenic acid having physiological activity, the levorotatory lactone must be employed in the synthesis; consequently, it is highly desirable to resolve the racemic-mixture. This may readily be done by converting the racemic mixture to the quinine salts of the acids and then separating the sale of the l-acid from that of d-acid by frictional crystallization. The quinine salt of the d-acid is converted to the sodium salt thereof and the liberated quinine removed from the solution. The sodium salt of the d-acid is hydrolyzed with acid and the l-lactone recovered by extracting it from the aqueous reaction medium. The quinine salt of the l-acid is likewise converted to the sodium salt thereof, the liberated quinine removed, and a neutral solution of the sodium salt is heated to convert the l-acid to the d,l-acid. The sodium salt of the d,l-acid obtained is then hydrolyzed with acid and the l-lactone isolated and recovered as before. Formerly the extraction of the l-lactone in both instances, i. e., the extraction of the l-lactone originally present and the extraction of that obtained by converting the d-lactone to the d,l-lactone, has been carried out by extracting the lactone from the reaction mass with ethyl ether. However, here, just as in the extraction of the original racemic mixture of the lactone, we have found that greatly superior results may be obtained by employing halogenated hydrocarbon solvents in place of ethyl ether to extract the l-lactone. In the specification and claims when we speak of employing a halogenated hydrocarbon solvent to extract the lactone from the reaction mass in which it is produced, we refer not only to the extraction of the original racemic mixture of the lactone but also to any other step in the preparation of the lactone wherein the lactone, either the dextrorotatory or the levorotatory form, is to be extracted from a reaction medium and that extraction may be accomplished by the use of ethyl ether, e. g., as was just mentioned above in the separation of the d-lactone from the l-lactone and the subsequent recovery of the l-lactone, and the conversion of the d-lactone to the d,l-lactone and the recovery of the l-lactone produced.

The recovery of the aldehyde and or" the lactone from the halogenated hydrocarbon solutions thereof may readily be accomplished by removing the solvent by means of distillation in any suitable manner, preferably under reduced pressure.

Although our invention has been described, particularly with reference to the production of 11,1):- dimethyl-fl-hydroxypropionaldehyde and a-hydroxy-;8,{i-dimethyl-v-butyrolactone, it is to be F understood that is is by no means limited to the production of these two compounds,sinceitis well known that there are compounds other than pantothenic acid which have to a certain extent the physiological activity of pantothenic acid. In the production of such compounds, some of the intermediate compounds, i. e., aldehydes and lactones, in the synthesis may be prepared similar to u,adimethyl-,G-hydroxypropionaldehyde and onhydroxy-B,B-dimethyl-Y-butyrolactonc. When such is the case, the aldehyde and the lactone, instead of being extracted from the respective reaction media with ethyl ether, may be extracted therefrom with much greater efficiency and safety by means of a halogenated hydrocarbon solvent in a manner as has been described hereinabove.

For a fuller understanding of the nature and objects of the invention, reference should be had to the following examples which are given merely to further illustrate the invention and are not to be construed in a limiting sense, all parts given being by weight:

Example I 15 parts of isobutyraldehyde were condensed with 17 parts of formalin (40% formaldehyde) in the usual manner in the presence of 13.7 parts of potassium carbonate. When the reaction was complete, 50 parts ethylene dichloride were added and the mixture stirred for about 20 minutes. The mixture was then allowed to separate into layers and the ethylene dichloride layer was removed and dried over sodium sulfate. The ethylene dichloride was then removed by means of vacuum distillation. The recovery of the can:- dimethyl B hydroxypropionaldehyde was substantially equivalent to the theoretical amount.

Example 11 20 parts of a,a-dimethyl-B-hydroxypropionaldehyde were reacted with a solution of 21.2 parts of sodium bisulfite. The bisulfite compound obtained was converted to the corresponding cyanohydrin by reacting it with 15.8 parts of potassium cyanide. The cyanohydrin was then converted to a-hydroxy-fl,,3-dimethyl-y-butyrolactone by acid hydrolysis. The solution of the lactone was neutralized to a pH of about 7.2, and the lactone then extracted therefrom with ethylene dichloride merely by mixing the solvent with the solution and drawing ofi the ethylene dichloride layer which separates. The solution was extracted'successively with 35, 25, and four 15-part portions of ethylene dichloride. The d,l-lactone was then recovered by removing the solvent under reduced pressure. A yield of lactone from 15% to 20% greater than that obtainable by continuously extracting the solution of the lactone with ethyl ether was obtained.

Example III A quantity of d,l-u-hydroxy-p,p-din1ethyl-7- Example V Similar extractions of 1-a-hYdIOX3I-flfi-dimethyl-*r-butyrolactone as were made in Example IV were made with methylene chloride and with chloroform. In each case the results obtained Were slightly better than when using ethylene dichloride.

From the above it can readily be seen that we have provided a much more eificient and far safer means of recovering ,0;-dimethyl-fi-hydroxypropionaldehyde and a-hydroxy-p,p-dimethyl-ybutyrolactone from the reaction masses in which they are produced than has hitherto been available.

Since certain changes may be made in carrying out the above process without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrated and not in a limiting sense.

Having described our invention, what we claim as new and desire to secure by Letters Patent is:

In the process of synthesizing a-hYdlOXY-fifidimethyl-Y-butyrolactone, the step which comprises extracting the same from the aqueous reaction mass in which it is produced by dissolving said lactone in methylene chloride.

ROLAND KAPP. FRANK D. PICKEL. LOUIS T. ROSENBERG.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 1,830,618 Pasternack, et a1. Nov. 3, 1931 2.434.246 Kapp et a1 Jan. 13, 1948 

